Polycarbonate containing compounds and methods related thereto

ABSTRACT

Disclosed herein are crosslinked polycarbonates, composition thereof and methods thereof. The crosslinked polycarbonates can be prepared from allyl or epoxy polycarbonates. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a continuation of U.S. application Ser. No.14/399,920, filed Nov. 7, 2014, now U.S. Pat. No. 9,580,548, which is aNational Stage of International Application No. PCT/US2013/040192, filedMay 8, 2013, which claims the benefit of U.S. Provisional ApplicationNo. 61/644,241, filed on May 8, 2012, which is incorporated herein byreference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with U.S. government support under grant numberCHE-0645737, awarded by the National Science Foundation (NSF), and undergrant number 5T32GM007628-33, awarded by the Pharmacology Training Grantunder a National Institute of Health (NIH) Training Grant. The U.S.government has certain rights in the invention.

BACKGROUND

A range of degradable polymers have been investigated for in vivoapplications.¹⁰⁻¹³ Poly(ester)s are most commonly studied, however theintroduction of side-chain functional groups is typically challengingand can limit their applicability in advanced applications.^(13,14)Poly(carbonate)s prepared by the ring-opening polymerization (ROP) of6-membered cyclic monomers have been widely explored for theseapplications and organocatalysis has provided efficient routes torealize a range of functionalized polymer structures.¹⁵⁻¹⁷ Recently, theexploration of a range of functional monomers and polymers has beenexplored from simple precursors giving access to unprecedented levels offunctional group incorporation.¹⁸⁻²⁰ Importantly, poly(carbonate)materials display slower degradation profiles with less toxic byproductsthan poly(ester)s thus making them ideal candidates as one of thebuilding blocks for advanced nanomaterials.¹⁴

Accordingly, described herein are poly(carbonate)s suitable fornanomaterials.

SUMMARY OF THE INVENTION

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocrosslinked polycarbonates, composition thereof and methods thereof.

Disclosed herein are compounds comprising a first and second allylfunctionalized polycarbonate. Also disclosed herein are compoundscomprising a crosslinked first and second allyl functionalizedpolycarbonate.

Also disclosed herein are compounds comprising a first and second epoxyfunctionalized polycarbonate. Also disclosed herein are compoundscomprising a crosslinked first and second epoxy functionalizedpolycarbonate.

Also disclosed herein are methods of crosslinking polycarbonatescomprising a) Providing a first and second allyl functionalizedpolycarbonate; and b) Crosslinking the first and second allylfunctionalized polycarbonate via a crosslinker.

Also disclosed herein are methods of crosslinking polycarbonatescomprising a) Providing a first and second epoxy functionalizedpolycarbonate; and b) Crosslinking the first and second epoxyfunctionalized polycarbonate via a crosslinker.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows nanoparticle formation via an intermolecular thiolene-clickreaction and the epoxide-a mine reaction with eitherP[(MAC)_(z)-co-(MTC-Et)_(y)] or the oxidized version.

FIGS. 2A and 2B show the DLS analysis data for both particles preparedwith amine-epoxide and the thiolene-click reaction along with thecorresponding TEM imagines of both particle systems: 2A: 5%amine-epoxide and 2B: 5% thiolene-click.

FIG. 3 shows the results for the kinetic results for ethyl carbonatehomopolymers.

FIG. 4 shows the results for the kinetic results for poly(MTC-Et) havinga [mon]:[cat]:[init] ration of 1250:4:50.

FIG. 5 shows the results for the kinetic results for poly(MTC-Et) havinga[mon]:[cat]:[init] ration of 1250:10:50.

FIG. 6 shows the results for the kinetic results for poly(MTC-Et) havinga [mon]:[cat]:[init] ration of 1250:4:50.

FIG. 7 shows the results for the kinetic results for poly(MTC-Et) havinga[mon]:[cat]:[init] ration of 1250:10:50.

FIG. 8 shows the results for the kinetic results for poly(MTC-Et) havinga [mon]:[cat]:[init] ration of 1250:4:50.

FIG. 9 shows the GPC trace of poly(MAC-co-MTC-Et) with comonomer ratio5:95 (MAC:MTC-Et).

FIG. 10 shows the GPC trace of poly(MAC-co-MTC-Et) with comonomer ratio10:90 (MAC:MTC-Et).

FIG. 11 shows the GPC trace of poly(MAC-co-MTC-Et) with comonomer ratio20:80 (MAC:MTC-Et).

FIG. 12 shows the kinetic results for poly(MTC-Et) with3-methyl-1-butanol with a [mon]:[cat]:[init] ration of 1250:4:50.

FIG. 13 shows the kinetic results for poly(MTC-Et) with3-methyl-1-butanol with a [mon]:[cat]:[init] ration of 1250:4:50.

FIG. 14 shows the results for the monomer conversion experimentdescribed herein.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” refers to the target ofadministration, e.g. an animal. Thus the subject of the herein disclosedmethods can be a vertebrate, such as a mammal, a fish, a bird, areptile, or an amphibian. Alternatively, the subject of the hereindisclosed methods can be a human, non-human primate, horse, pig, rabbit,dog, sheep, goat, cow, cat, guinea pig, fish, bird, or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects. In some aspects of the disclosedmethods, the subject has been diagnosed with a need for treatment of oneor more muscle disorders prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with aneed for promoting muscle health prior to the administering step. Insome aspects of the disclosed method, the subject has been diagnosedwith a need for promoting muscle health prior, promote normal musclefunction, and/or promote healthy aging muscles to the administeringstep.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. In addition, this termincludes palliative treatment, that is, treatment designed for therelief of symptoms rather than the curing of the disease, pathologicalcondition, or disorder; preventative treatment, that is, treatmentdirected to minimizing or partially or completely inhibiting thedevelopment of the associated disease, pathological condition, ordisorder; and supportive treatment, that is, treatment employed tosupplement another specific therapy directed toward the improvement ofthe associated disease, pathological condition, or disorder. In variousaspects, the term covers any treatment of a subject, including a mammal(e.g., a human), and includes: (i) preventing the disease from occurringin a subject that can be predisposed to the disease but has not yet beendiagnosed as having it; (ii) inhibiting the disease, i.e., arresting itsdevelopment; or (iii) relieving the disease, i.e., causing regression ofthe disease. In one aspect, the subject is a mammal such as a primate,and, in a further aspect, the subject is a human. The term “subject”also includes domesticated animals (e.g., cats, dogs, etc.), livestock(e.g., cattle, horses, pigs, sheep, goats, fish, bird, etc.), andlaboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly,etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with cancer” means having been subjected to a physicalexamination by a person of skill, for example, a physician, and found tohave a condition that can be diagnosed or treated by a compound orcomposition that can treat or prevent cancer. As a further example,“diagnosed with a need for treating or preventing cancer” refers tohaving been subjected to a physical examination by a person of skill,for example, a physician, and found to have a condition characterized bycancer or other disease wherein treating or preventing cancer would bebeneficial to the subject. Such a diagnosis can be in reference to adisorder, such as cancer or duodenal ulcers, and the like, as discussedherein.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto cancer) based upon an earlier diagnosis by a person of skill andthereafter subjected to treatment for the disorder. It is contemplatedthat the identification can, in one aspect, be performed by a persondifferent from the person making the diagnosis. It is also contemplated,in a further aspect, that the administration can be performed by one whosubsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, target receptor, or other biological entitytogether in such a manner that the compound can affect the activity ofthe target (e.g., receptor, transcription factor, cell, etc.), eitherdirectly; i.e., by interacting with the target itself, or indirectly;i.e., by interacting with another molecule, co-factor, factor, orprotein on which the activity of the target is dependent.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side affects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “EC₅₀,” is intended to refer to the concentration ordose of a substance (e.g., a compound or a drug) that is required for50% enhancement or activation of a biological process, or component of aprocess, including a protein, subunit, organelle, ribonucleoprotein,etc. EC₅₀ also refers to the concentration or dose of a substance thatis required for 50% enhancement or activation in vivo, as furtherdefined elsewhere herein. Alternatively, EC₅₀ can refer to theconcentration or dose of compound that provokes a response halfwaybetween the baseline and maximum response. The response can be measuredin a in vitro or in vivo system as is convenient and appropriate for thebiological response of interest. For example, the response can bemeasured in vitro using cultured muscle cells or in an ex vivo organculture system with isolated muscle fibers. Alternatively, the responsecan be measured in vivo using an appropriate research model such asrodent, including mice and rats. The mouse or rat can be an inbredstrain with phenotypic characteristics of interest such as obesity ordiabetes. As appropriate, the response can be measured in a transgenicor knockout mouse or rat wherein a gene or genes has been introduced orknocked-out, as appropriate, to replicate a disease process.

As used herein, “IC₅₀,” is intended to refer to the concentration ordose of a substance (e.g., a compound or a drug) that is required for50% inhibition or diminuation of a biological process, or component of aprocess, including a protein, subunit, organelle, ribonucleoprotein,etc. IC₅₀ also refers to the concentration or dose of a substance thatis required for 50% inhibition or diminuation in vivo, as furtherdefined elsewhere herein. Alternatively, IC₅₀ also refers to the halfmaximal (50%) inhibitory concentration (IC) or inhibitory dose of asubstance. The response can be measured in a in vitro or in vivo systemas is convenient and appropriate for the biological response ofinterest. For example, the response can be measured in vitro usingcultured muscle cells or in an ex vivo organ culture system withisolated muscle fibers. Alternatively, the response can be measured invivo using an appropriate research model such as rodent, including miceand rats. The mouse or rat can be an inbred strain with phenotypiccharacteristics of interest such as obesity or diabetes. As appropriate,the response can be measured in a transgenic or knockout mouse or ratwherein a gene or genes has been introduced or knocked-out, asappropriate, to replicate a disease process.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

As used herein, the terms “linker” and “crosslinker” are usedinterchangeably.

B. Compounds and Compositions

For the first time described herein is the formation of functionalizedpoly(carbonate) particles with an established intermolecularcross-linking process. Six types of ‘nanosponges’ were prepared with thedifferentiation in crosslinking density and crosslinking chemistry. Theintermolecular chain crosslinking process was investigated via theepoxide amine reaction and the thiol-ene click reaction. Well-definedfunctionalized polycarbonate copolymers from organocatalytic synthesisand Sn(OTf)₂ metal catalyzed reactions were critical to performcontrolled crosslinking reactions to give particles in nanoscopic sizesof 150-220 nm for the thiolene-click reaction and 160-230 nm for theepoxide amine reaction. The resulting nanoscopic sizes are a result ofthe chosen equivalencies of the diamine or dithiol-crosslinking partnerto provide an example of the intermolecular cross-linking reaction.

Disclosed herein are compounds comprising a first and second allylfunctionalized polycarbonate. Also disclosed herein are compoundscomprising a crosslinked first and second allyl functionalizedpolycarbonate. Also disclosed herein are compounds comprising a firstallyl functionalized polycarbonate.

Disclosed herein are compounds comprising a first and second epoxyfunctionalized polycarbonate. Also disclosed herein are compoundscomprising a crosslinked first and second epoxy functionalizedpolycarbonate. Also disclosed herein are compounds comprising a firstepoxy functionalized polycarbonate.

Also disclosed herein are nanosponges comprising the disclosedcompounds. Also disclosed herein are nanoparticles comprising thedisclosed compounds. Also disclosed herein are macroscopic networkscomprising the disclosed compounds. Also disclosed herein are hydrogelscomprising the disclosed compounds.

In one aspect, the compounds comprise a crosslinker.

In one aspect, the crosslinker comprises at least two moieties that canbe reacted with an allyl. In another aspect, the crosslinker comprisesat least two moieties that can be reacted with an epoxy. In yet anotheraspect, the crosslinker comprises at least one moiety that can bereacted with an epoxy and at least one moiety that can be reacted withan allyl. In yet another aspect, the crosslinker comprises at least oneamine moiety. In yet another aspect, the crosslinker comprises at leasttwo amine moieties. In yet another aspect, the crosslinker comprises atleast one thiol moiety. In yet another aspect, the crosslinker comprisesat least two thiol moieties. In yet another aspect, the crosslinkercomprises at least one thiol moiety and at least one amine moiety.

In one aspect, the crosslinker comprises one or more ether bonds. Inanother aspect, the crosslinker comprises two ether bonds.

In yet another aspect, the crosslinker has the structure

wherein n is from 1 to 1000.

In yet another aspect, the crosslinker has the structure

In yet another aspect, the crosslinker has the structure

wherein n is from 1 to 1000.

In yet another aspect, the crosslinker has the structure

In one aspect, the first and second allyl functionalized polycarbonateare the same. In another aspect, the first and second allylfunctionalized polycarbonates are the different.

In one aspect, the first and second allyl functionalized polycarbonateare copolymers.

In one aspect, the first and second epoxy functionalized polycarbonateare the same. In another aspect, the first and second epoxyfunctionalized polycarbonates are the different.

In one aspect, the first and second epoxy functionalized polycarbonateare copolymers.

In one aspect the first and/or second allyl functionalized polycarbonatecan be a co-polymer. The copolymer comprises at least one part allylmonomer and at least one part non-allyl monomer. The non-allyl monomerdoes not react with the crosslinker. In one aspect, the non-allylmonomer is present in a larger amount than the allyl monomer in thecopolymer. For example, the non-allyl monomer can be present at least in60%, 70%, 75%, 80%, 85%, 90%, 95% or 98% in the copolymer.

In one aspect the first and/or second epoxy functionalized polycarbonatecan be a co-polymer. The copolymer comprises at least one part epoxymonomer and at least one part non-epoxy monomer. The non-epoxy monomerdoes not react with the crosslinker. In one aspect, the non-epoxymonomer is present in a larger amount than the epoxy monomer in thecopolymer. For example, the non-epoxy monomer can be present at least in60%, 70%, 75%, 80%, 85%, 90%, 95% or 98% in the copolymer.

In one aspect, the wherein the first allyl functionalized polycarbonatehas the formula

wherein y is 1 to 1000 and z is 1 to 1000.

In one aspect, the wherein the second allyl functionalized polycarbonatehas the formula

wherein y is 1 to 1000 and z is 1 to 1000.

In one aspect, the crosslinked polycarbonate has the structure

wherein each y is individually 1 to 1000, each z is individually 1 to1000, and n is 1 to 1000.

In one aspect, the first epoxy functionalized polycarbonate has thestructure

whereie y is 1 to 1000 and z is 1 to 1000.

In one aspect, the second epoxy functionalized polycarbonate has thestructure

wherein y is 1 to 1000 and z is 1 to 1000.

In one aspect, the crosslinked polycarbonate has the structure

In one aspect, y is 1 to 1000. In another aspect, y is 1 to 500. In yetanother aspect, y is 1 to 300. In yet another aspect, y is 1 to 100. Inyet another aspect, y is 1 to 50. In yet another aspect, y is 1 to 25.

In one aspect, z is 1 to 1000. In another aspect, z is 1 to 500. In yetanother aspect, z is 1 to 300. In yet another aspect, z is 1 to 100. Inyet another aspect, z is 1 to 50. In yet another aspect, z is 1 to 25.

In another aspect, y is 1 to 500 and z is 1 to 500. In yet anotheraspect, y is 1 to 300 and z is 1 to 300. In yet another aspect, y is 1to 100 and z is 1 to 100. In yet another aspect, y is 1 to 50 and z is 1to 50. In yet another aspect, y is 1 to 25 and z is 1 to 25.

In one aspect, n is 1 to 500. In yet another aspect, n is 1 to 300. Inyet another aspect, n is 1 to 100. In yet another aspect, n is 1 to 50.In yet another aspect, n is 1 to 25.

In one aspect, the first allyl functionalized polycarbonate comprises atleast 75% y. In another aspect, the first allyl functionalizedpolycarbonate comprises at least 80% y. In yet another aspect, the firstallyl functionalized polycarbonate comprises at least 85% y. In yetanother aspect, the first allyl functionalized polycarbonate comprisesat least 90% y. In yet another aspect, the first allyl functionalizedpolycarbonate comprises at least 95% y.

In one aspect, the first epoxy functionalized polycarbonate comprises atleast 75% y. In another aspect, the first epoxy functionalizedpolycarbonate comprises at least 80% y. In yet another aspect, the firstepoxy functionalized polycarbonate comprises at least 85% y. In yetanother aspect, the first epoxy functionalized polycarbonate comprisesat least 90% y. In yet another aspect, the first epoxy functionalizedpolycarbonate comprises at least 95% y.

In one aspect, the compounds disclosed herein can comprise a targetingpeptide. The targeting peptide can be covalently bonded to the compound.In one aspect, the targeting peptide can be covalently bonded to acrosslinker. In one aspect, the compound comprises a crosslinked firstand second epoxy functionalized polycarbonate and a targeting peptidecovalently bonded to a crosslinker. In another aspect, the compoundcomprises a crosslinked first and second allyl functionalizedpolycarbonate and a targeting peptide covalently bonded to acrosslinker.

In one aspect, the targeting peptide is a cancer targeting peptide. Suchcancer targeting peptides are known in the art. In one aspect, thecancer targeting peptide is N-methylmorpholine.

In one aspect, the compound has the structure

wherein each a is individually 1 to 1000, each b is individually 1 to1000, and each c is 1 to 1000.

In another aspect, the compound has the structure

wherein each a is individually 1 to 1000, each b is individually 1 to1000, and each c is 1 to 1000.

In one aspect, a is 1 to 1000. In another aspect, a is 1 to 500. In yetanother aspect, a is 1 to 300. In yet another aspect, a is 1 to 100. Inyet another aspect, a is 1 to 50. In yet another aspect, a is 1 to 25.

In one aspect, b is 1 to 1000. In another aspect, b is 1 to 500. In yetanother aspect, b is 1 to 300. In yet another aspect, b is 1 to 100. Inyet another aspect, b is 1 to 50. In yet another aspect, b is 1 to 25.

In one aspect, c is 1 to 1000. In another aspect, c is 1 to 500. In yetanother aspect, c is 1 to 300. In yet another aspect, c is 1 to 100. Inyet another aspect, c is 1 to 50. In yet another aspect, c is 1 to 25.

Also disclosed is a nanoparticle comprising the compounds comprising acrosslinked first and second epoxy functionalized polycarbonate and atargeting peptide covalently bonded to a crosslinker. In one aspect, thenanoparticle can further comprise a therapeutic agent, prophylacticagent, or diagnostic agent, or a mixture thereof. In one aspect, thenanoparticle further comprises a cancer therapeutic agent, such aspaclitaxel.

In one aspect, the crosslinked polycarbonate disclosed herein is ananosponge. In another aspect, the crosslinked polycarbonate disclosedherein is a nanoparticle. In yet another aspect, the crosslinkedpolycarbonate disclosed herein is a macroscopic network.

In one aspect, the compounds and compositions disclosed herein cancomprise a hydroxyl terminated polymer, such a hydroxyl terminated PEG.The hydroxyl terminated polymer can be hydrophilic. In one aspect, thehydroxyl terminated polymer can be covalently bonded to the compound.

In one aspect, the compound can have the structure

wherein each y independently is 1 to 1000 and each z independently is 1to 1000.

Also disclosed herein are macroscopic networks comprising the disclosedcompounds comprising a hydroxyl terminated polymer. These macroscopicnetworks can be altered via reversible trans-esterification reactions,thereby changing the properties of the macroscopic network. An exampleof such technology is described by Montarnal et al. (Science, 334, 965(2011), which is hereby incorporated by references in its entirety.

Also disclosed is a pharmaceutical composition comprising a compound orcomposition disclosed herein and an effective amount of a therapeuticagent, prophylactic agent, or diagnostic agent, or a mixture thereof,and a pharmaceutically acceptable carrier. In one aspect, the disclosedcompounds and pharmaceutical compositions can be co-administered withone or more therapeutic agents, prophylactic agents, or diagnosticagents.

C. Methods of Making Compound and Compositions

Disclosed herein is a method of crosslinking polycarbonates comprising:a) providing a first and second allyl functionalized polycarbonate; andb) crosslinking the first and second allyl functionalized polycarbonatevia a crosslinker.

Also disclosed herein is a method of crosslinking polycarbonatescomprising: a) providing a first and second epoxy functionalizedpolycarbonate; and b) crosslinking the first and second epoxyfunctionalized polycarbonate via a crosslinker.

Also disclosed herein is a method of crosslinking polycarbonatescomprising: a) providing a first epoxy functionalized polycarbonate; b)providing a first allyl functionalized polycarbonate; and c)crosslinking the first epoxy functionalized polycarbonate and the firstallyl functionalized polycarbonate via a crosslinker.

In one aspect, the methods comprise the use of a Sn catalyst.

Disclosed herein are compounds made from the methods disclosed herein.Also disclosed are composition comprising compounds made from themethods disclosed herein. Also disclosed are nanoparticles comprisingcompounds made from the methods disclosed herein.

D. Methods of Use

Also disclosed herein is a method of delivering a therapeutic agent,prophylactic agent, or diagnostic agent to a subject in need thereofcomprising administering a composition comprising a compound orcomposition disclosed herein comprising a therapeutic agent,prophylactic agent, or diagnostic agent. In one aspect, the compositionis a nanosponge or nanoparticle. In another aspect, the composition is amacroscopic network. In yet another aspect, the composition is apharmaceutical composition as disclosed herein. In one aspect, theadministration is oral administration.

In one aspect, the subject has been diagnosed with a need for theadministration of a therapeutic agent, prophylactic agent, or diagnosticagent.

E. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for treating or preventing a disease, such as cancer,comprising combining a therapeutically effective amount of a disclosedcompound or compositions or product of a disclosed method with apharmaceutically acceptable carrier or diluent.

In a further aspect, the medicament comprises a disclosed compound orcomposition.

F. Kits

Also disclosed herein are kits comprising one or more of the disclosedcompounds or compositions, and one or more of: a) at least one canceragent, b) instructions for treating a disorder associated with cancer,or c) instructions for administering the one or more disclosed compoundsor compositions.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases are commercially available, orcan be prepared according to literature procedures or as illustratedherein.

The following exemplary compounds of the invention were synthesized. TheExamples are provided herein to illustrate the invention, and should notbe construed as limiting the invention in any way.

a. Example 1

(a) Experimental Section:

Materials. CDCl₃ and (−)-sparteine were dried over CaH₂, distilled,degassed and stored under inert atmosphere. Benzyl alcohol was dried andstored over 4 Å molecular sieves under inert atmosphere. Methylenechloride was purified over an Innovative Technology SPS alumina solventcolumn and degassed before use.5-Methyl-5-allyloxycarbonyl-1,3-dioxan-2-one (MAC) was synthesized asreported previously by Hu, X et al (J. Polym. Sci., Part A: Polym. Chem.2007, 45, 5518-5528), recrystallized several times before use and driedover CaH₂ in dry THF at 50-60° C.1-(3,5-Bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea was synthesizedas previously reported by Pratt, R et al. (Macromolecules 2006, 39,7863-7871) then dried over calcium hydride in dry tetrahydrofuran andrecrystallized from dry methylene chloride. Silica Gel (pore size=40 Å)was obtained from Fisher Scientific and used as received. All othersolvents and chemicals were obtained from Sigma Aldrich or FisherScientific and used as received.

General considerations. Polymerizations were performed under inertatmosphere in a glovebox. ¹H NMR and ¹³C NMR spectra at Warwick wererecorded on a Bruker DPX-300, DPX-400, DRX-500 or AV II-700 spectrometerat 293K. Chemical shifts are reported as δ in parts per million (ppm)and referenced to the residual solvent signal (CDCl₃: ¹H, δ=7.26 ppm;¹³C, δ=77.16 ppm; (CD₃)₂SO: ¹H, δ=2.50; ¹³C, δ=39.52). Gel-permeationchromatography (GPC) was used to determine the molecular weights andpolydispersities of the synthesized polymers. GPC in THF was conductedon a system composed of a Varian 390-LC-Multi detector suite fitted withdifferential refractive index (DRI), light scattering (LS), andultraviolet (UV) detectors equipped with a guard column (Varian PolymerLaboratories PLGel 5 μM, 50×7.5 mm) and two mixed D columns (VarianPolymer Laboratories PLGel 5 μM, 300×7.5 mm). The mobile phase waseither tetrahydrofuran eluent or tetrahydrofuran with 5% triethylamineeluent at a flow rate of 1.0 mL·min⁻¹, and samples were calibratedagainst Varian Polymer Laboratories Easi-Vials linear poly(styrene)standards (162−3.7×10⁵ g mol⁻¹) using Cirrus v3. The dymamic lightscattering (DLS) measurements were performed by Mr Jerry CabinessfromNanosight Inc. and were measured in CH₂Cl₂ as solvent.

Samples for transmission electron microscopy (TEM) imaging were preparedby dissolving 0.5 mg nanoparticles in a solution of 1 mL isopropanol,0.3 mL acetonitrile and 0.2 mL toluene. The samples were sonicated for 5min and stained with 3 drops of 3% phosphotungstic acid. The carbongrids were prepared by slowly dipping an Ultrathin Carbon Type-A 400Mesh Copper Grid (Ted Pella, Inc., Redding, Calif.) into the particlesolution three times and air drying the grid at room temperature. APhilips CM20T transmission electron microscope operating at 200 kV inbright-field mode was used to obtain TEM micrographs of the polymericnanoparticles.

(b) General Procedure for Ring-Opening Polymerization

Polymerizations were completed in glovebox. A solution of ethyl5-methyl-2-oxo-1,3-dioxane-5-carboxylate (397 mg, 2.112 mmol) and allyl5-methyl-2-oxo-1,3-dioxane-5-carboxylate (106 mg, 0.528 mmol) in CH₂Cl₂(0.84 mL) was added to a stirred solution of1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea (97.8 mg, 0.264mmol), benzyl alcohol (13.7 μL, 0.132 mmol) and sparteine (30.3 μL,0.132 mmol) in CH₂Cl₂ (0.84 mL). After the allotted period of time, thereaction was twice precipitated from CH₂Cl₂ into hexanes and dried underreduced pressure. Residual catalyst impurities were removed by columnchromatography on silica (80% hexanes, 20% ethyl acetate). Purifiedpolymer was dried under reduced pressure. ¹H NMR (400 MHz, CDCl₃/TMS,ppm) δ: 7.37 (m, OBn-ArH), 5.9 (m, CH_(vinyl)), 5.3 (m, CH_(2-vinyl)),5.15 (s, OBn-CH₂), 4.64 (m, OCH₂CHCH₂), 4.40-4.18 (m, MAC & MTC-et,OC(O)OCH₂), 1.30-1.22 (m, MAC, CH₃; MTC-et, OCH₂CH₃)

(c) General Procedure for Oxidation of Copolymers

3-Chloroperoxybenzoic acid (30.4 mg, 0.176 mmol) was added to a stirredsolution of poly(MTC-Et, MTC-allyl) (0.200 g, 0.214 mmol) in CH₂Cl₂ (3.7mL). The mixture stirred for 48 hours at room temperature. Residual3-chloroperoxybenzoic acid was removed by dialysis againstdichloromethane using Spectra/Por Dialysis Membrane (MWCO=2,000) toyield pure polymer (0.180 g). ¹H NMR (400 MHz, CDCl₃/TMS, ppm) δ: Thesignificant change is the disappearance of the allylic protons at 5.9and 5.3 ppm and the emergence of small broad peaks at 3.19, 2.82, and2.63 ppm due to formation of the epoxide ring.

(d) Nanoparticle Formation:

Poly(5% MTC-allyl, 95% MTC-et) nanoparticle formation using thiol-enecross-linking with 3,6-dioxa-1,8-octanedithiol

3,6-dioxa-1,8-octane-dithiol (18.4 μL, 0.113 mmol) was added to asolution of poly(5% MTC-allyl, 95% MTC-Et) (100 mg, M_(n)=5.0 kDa,PDI=1.56) in CH₂Cl₂ (8.7 mL). The reaction mixture refluxed for 12 hoursat 45° C. Residual cross-linker was removed by dialyzing with SnakeSkinPleated Dialysis Tubing (MWCO=10,000) against CH₂Cl₂ to yield particles(96 mg). ¹H NMR (400 MHz, CDCl₃/TMS, ppm) δ: The significant change isthe disappearance of the allylic protons at 5.9 and 5.3 ppm and theemergence of peaks at 3.64 ppm due to the methylene protons adjacent tothe oxygens in the crosslinker and 2.73-2.68 ppm due to methyleneprotons adjacent to the sulfide functionality.

b. Discussion

Functionalized linear polycarbonates prepared using organocatalyticsynthesis and Sn(OTf)₂ metal catalyzed methods where furtherpost-modified via thiolene-click reactions and epoxide-amine reactionsto form nanoparticles by an intermolecular cross-linking approaches.

Value-driven engineering and the synthesis of biomaterials forapplications in tissue engineering, wound healing and drug delivery isone of the driving forces in the development of defined andfunctionalized materials. While the preparation of poly(ester) andpoly(carbonate) based particles has been mainly driven by precipitationprocesses, chemically driven nanoparticle synthesis has given theopportunity to control sizes and architectural nature of the particles.Especially intramolecular^(1,2) and inter chain-crosslinkingprocesses^(3,4) have shown to be useful routes. Some of us havedemonstrated that the intermolecular chain cross-linking of side-chainfunctional poly(ester)s derived by ring-opening polymerization ofsubstituted δ-valerolactone monomers provides a facile methodology forversatile nanoparticle preparation.⁵⁻⁸ This methodology affordscontrolled nanoparticle sizes that can be varied via the percentiles ofside-chain functionalities into the linear polyester precursor.Furthermore, the morphology and size can be controlled with the amountof difunctionalized cross-linking units, reacting with the side-chainfunctionality of the polymer. With this, functionalized particles thatare further post-modified to react with targeting units and turned intodrug delivery systems upon encapsulation can be tested for theirbiological response.^(8,9)

Herein we demonstrate that for the first time, allyl- andepoxide-functional aliphatic poly(carbonate)s can be applied in theintramolecular chain crosslinking process for the synthesis ofpoly(carbonate) nanosponges (FIG. 1).

Extension of the organocatalytic methods for ROP of5-methyl-5-allyloxycarbonyl-1,3-dioxane-2-one (MAC) to preparecopolymers with 5-methyl-5-ethyloxycarbonyl-1,3-dioxane-2-one (MTC-Et)to provide lower functional group densities was undertaken.²¹ With thisapproach, the allyl functionalities are, for example, excellent groupswith which to form particles in intermolecular chain cross-linkingreactions and other post-modifications using thiol-ene click chemistry.Furthermore, as previously demonstrated by Storey and co-workers,²² theoxidation of allyl-functional poly(carbonate)s with m-CPBA results inthe formation of the epoxide-functional polymers to provide analternative group that has been proven to be very valuable to thesynthesis of nanoparticles and functionalization reactions in surfacelabeling. Our initial studies focused on the synthesis of a range ofcopolymers of MAC and MTC-Et cyclic carbonate monomers with differentincorporations of MAC using the previously optimized ROP conditions forMAC homopolymerization.²² To this end, a series of copolymers withincreasing amounts of MAC to MTC-Et were prepared (Table 1) initiatedfrom benzyl alcohol using the (−)—sparteine/thiourea catalyst system(Scheme 1).

In another appraoch to circumvent complicated glove box proceduresassociated with systems that are catalyzed with organo catalysts, wehave found a practical approach to facilitate well-controlledpolycarbonate polymers with use of Sn(OTf)₂. The Sn endgroup can beremoved by quenching the reaction with MeOH.

The observed copolymers showed a good control in molecular weightalthough slightly broad dispersities that are a consequence of highmolecular weight tailing of the polymer distributions (see SupportingInformation). Incorporation of the MAC monomer, which contains theallylfunctionality, was consistent with the monomer feed ratios asconfirmed by ¹H NMR spectrscopy. The ability of the copolymers (Table 1)to form nanoparticles was investigated via the previously developedthiol-ene “click” chemistry and epoxide-aminereaction.

TABLE 1 Ring -opening copolymerization of MAC and MTC (^(a)Allpolymerizations were conducted in dichloromethane at 25° C., [monomer] =1.6M, [monomer]/[initiator] = 20 using benzyl alcohol as initiator with10 mol % TU and 5 mol % (−)-sparteine as catalysts. Molecular weight andpolydispersity were determined using GPC calibrated with poly(styrene)standards in chloroform. Conversion and molecular weight were determinedby NMR.) Polymer Composition Monomer (MTC- Conversion M_(n)(GPC)M^(n)(NMR) Et:MAC) (%) (KDa) (KDa) PDI 95:5  >95 4.7 5.0 1.56 90:10 >955.0 5.3 1.25 80:20 >95 4.9 6.4 1.39

The Reaction of 8 equivalents of the dithiolethylenoxide cross-linker tothe P[(MAC)_(z)-co-(MTC-Et)_(y)] functionalized polymer containing 5%,10% and 20% MAC and the allyl functionality led to the observation ofwell-defined poly(carbonate) nanosponges (Supporting Information). TEMand DLS analysis showed that the increasing amount of cross-linker inthe polymer backbone led to larger particle that displayednumber-average solution hydrodynamic diameters, D_(h) of ˜220 nm for the20% cross-linker-containing particles, in contrast to smaller particlesizes of D_(h)=150 nm for the particles prepared with 5% MAC comonomerincorporated. The DLS data suggested that the higher crosslinking ledalso to a higher degree of particle deviation (FIG. 2). In comparison tothiolene-“click” reactions with analogous poly(ester) linear polymers,the poly(carbonate)-derived particles are smaller than expected,attributed to a lower degree of polymerization of the poly(carbonate)copolymers than those reported from the poly(ester) polymers and itsanalogs.

As an alternative methodology, particle formation using epoxide-aminecross-linking chemistry, analogous to the functionalized poly(ester)particles, was investigated. The MAC-containing copolymers were fullyepoxidized by treatment with 1.2 eq. mCPBA in CH₂Cl₂ to form thesuitable linear precursor. The disappearance of the characteristic vinylresonances in the range δ=5.9-5.3 ppm was observed with the appearanceof resonances that are clearly attributable to the formation ofepoxide-functional polymers at δ=3.19, 2.82, and 2.63 ppm (SupportingInformation). Other resonances in the ¹H NMR spectrum of the polymersdid not change and the same chain length was determined by end groupanalysis.

Reaction of the functionalized copolymers containing 5%, 10% and 20%epoxide pendant functional groups with also 8 eq. diaminoethyleneoxidewas performed to intermolecularly crosslink the polymers (SupportingInformation). Analysis of the resultant nanosponges, again via ¹H-NMRspectroscopy, TEM and DLS, demonstrated that particles slightlyincreased sizes of D_(h)=230 nm for the particles with 20% cross-linkingin contrast to D_(h)=160 nm for particles prepared from the lowestcross-linking density available in the study (FIG. 2). In comparison toanalogouspoly(ester) materials, the particle sizes are smaller, againattributed to the lower degree of polymerization in contrast to thepreviously investigated polyester materials.

In summary, we have prepared functionalized poly(carbonate) copolymersof 5-methyl-5-allyl-oxycarbonyl-1,3-dioxan-2-one (MAC) and5-Methyl-5-ethyloxycarbonyl-1,3-dioxane-2-one (MTC-Et) viaorganocatalytic synthesis under mild conditions using a thiourea and(−)-sparteine catalyst system. The pendant allyl groups were utilized ascross-linking partners in thiol-ene click reactions forming nanospongesin the sizes of 150-220 nm depending on the cross-linking density of thelinear precursor with 5%, 10% and 20% of pendant allyl groupsincorporated. The oxidation of the allyl groups in the copolymers toepoxides was successful and the following cross-linking reaction withdiaminesenabled the synthesis of thenanosponge particles in size rangesof 160-230 nm using an alternative epoxide-amine chemistry. For thefirst time we have demonstrated the formation of functionalizedpoly(carbonate) particles with the established intermolecularcross-linking process.

c. Ethyl Carbonate Homopolymer Synthesis

(a) Synthesis of Ethyl Polycarbonate Homopolymer

Added MTC-Et (100 mg, 0.531 mmol), Sn(OTf)₂ (5 uL, 0.037 M in THF), andbenzyl alcohol (14.7 uL, 1.7 M in THF) to a nitrogen-purged, flame-dried25-mL round bottom flask. Two additional milliliters of dry THF wereadded to dissolve everything. Reaction stirred at room temperature for48 hours. NO RXN

(b) Synthesis of Ethyl Polycarbonate Homopolymer

([mon]:[cat]:[init]=1250:1:50)

A 1-dram vial was equipped with stir bar, capped with rubber septum,flame dried and nitrogen purged. MTC-Et (0.500 g, 2.660 mmol) andSn(OTf)₂ (0.89 mg, 0.0213 mmol) were added to the vial, and the vial wasnitrogen purged once more. The vial was added to 65° C. oil bath andallowed to stir for 5 minutes before adding the benzyl alcohol (11 uL,0.106 mmol) and allowing to stir at 65° C. overnight to yield polymernext morning.

(C) Synthesis of Ethyl Polycarbonate Homopolymer

([mon]:[cat]:[init]=1250:1:50)

Added Sn(OTf)₂ (57.5 uL, 0.037 M in THF) and benzyl alcohol (62.6 uL,1.7 M in THF) to a nitrogen-purged, flame-dried 25-mL round bottomflask. The catalyst/initiator mixture was allowed to stir at roomtemperature for several minutes before adding MTC-Et (500 mg, 2.660mmol). An additional 500 uL dry THF was required to dissolve allreagents. Reaction stirred at room temperature for 5 days. Reaction wasquenched by adding dichloromethane and hexanoic acid. The polymer waspurified by crashing out in hexanes to yield polymer (PDI=1.11).

d. Ethyl Carbonate Homopolymer Kinetics

([mon]:[cat]:[init]=1250:1:50)

A 1-dram vial was equipped with stir bar, capped with septum, flamedried, and nitrogen purged. Sn(OTf)₂ (0.17 mL, 0.0124 M in ethylacetate) and benzyl alcohol (0.17 mL, 0.611 M in ethyl acetate) wereadded to the vial via syringe, and ethyl acetate was evaporated off vianitrogen flow. MTC-Et (500 mg, 2.660 mmol) was added and allowed to stirat 70° C. At each time point, a small amount of the reaction was removedvia syringe and analyzed by NMR. The results for the kinetics for ethylcarbonate homopolymers can be seen in FIG. 3.

e. Kinetics of Poly(MTC-Et) ([MON]:[CAT]:[INIT]=1250:4:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (7.5 mg, 0.018mmol) was weighed directly into the flask followed by the addition ofMTC-Et (1.00 g, 5.319 mmol). The flask was sealed with rubber septum,argon purged and set to stir in a 70° C. oil bath. Benzyl alcohol (22uL, 0.210 mmol) was added to the flask via microsyringe. At each timepoint, a small amount of the reaction was removed via syringe andanalyzed by NMR. The results for the kinetics of poly(MTC-Et) having a[mon]:[cat]:[init] ration of 1250:4:50 can be seen in FIG. 4.

f. Kinetics of Poly(MTC-Et) ([MON]:[CAT]:[INIT]=1250:10:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (17.7 mg, 0.042mmol) was weighed directly into the flask followed by the addition ofMTC-Et (1.00 g, 5.319 mmol). The flask was sealed with rubber septum,argon purged and set to stir in a 70° C. oil bath. Benzyl alcohol (22uL, 0.210 mmol) was added to the flask via microsyringe. At each timepoint, a small amount of the reaction was removed via syringe andanalyzed by NMR. The results for the kinetics of poly(MTC-Et) havinga[mon]:[cat]:[init] ration of 1250:10:50 can be seen in FIG. 5.

g. Kinetics of Poly(MTC-Et) ([MON]:[CAT]:[INIT]=1250:4:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (7.5 mg, 0.018mmol) was weighed directly into the flask followed by the addition ofMTC-Et (1.00 g, 5.319 mmol). The flask was sealed with rubber septum,argon purged and set to stir in a 70° C. oil bath. Benzyl alcohol (22uL, 0.210 mmol) was added to the flask via microsyringe. At each timepoint, a small amount of the reaction was removed via syringe andanalyzed by NMR. The results for the kinetics of poly(MTC-Et) having a[mon]:[cat]:[init] ration of 1250:4:50 can be seen in FIG. 6.

h. Kinetics of Poly(MTC-Et) ([MON]:[CAT]:[INIT]=1250:10:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (17.7 mg, 0.042mmol) was weighed directly into the flask followed by the addition ofMTC-Et (1.00 g, 5.319 mmol). The flask was sealed with rubber septum,argon purged and set to stir in a 70° C. oil bath. Benzyl alcohol (22uL, 0.210 mmol) was added to the flask via microsyringe. At each timepoint, a small amount of the reaction was removed via syringe andanalyzed by NMR. The results for the kinetics of poly(MTC-Et) havinga[mon]:[cat]:[init] ration of 1250:10:50 can be seen in FIG. 7.

i. Kinetics of Poly(MTC-Et) ([MON]:[CAT]:[INIT]=1250:4:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (6.8 mg, 0.016mmol) was weighed directly into the flask. The flask was sealed withrubber septum, argon purged and set to stir in a 70° C. oil bath. Benzylalcohol (22 uL, 0.210 mmol) was added to the flask via microsyringe andthe catalyst/iniator solution was allowed to stir at 70° C. for 30minutes. MTC-Et (1.00 g, 5.319 mmol) was added to the solution andallowed to stir. At each time point, a small amount of the reaction wasremoved via syringe and analyzed by NMR. The results for the kinetics ofpoly(MTC-Et) having a [mon]:[cat]:[init] ration of 1250:4:50 can be seenin FIG. 8.

j. Synthesis of Carbonate Copolymers

(a) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:1:50)

([mon]:[cat]:[init]=1250:1:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (0.88 mg, 0.0213mmol) was weighed directly into the flask. The flask was sealed withrubber septum, argon purged and set to stir in a 65° C. oil bath. Benzylalcohol (11 uL, 0.105 mmol) was added to the flask via microsyringe andallowed to stir for 5 minutes. MTC-allyl (105 mg, 0.525 mmol) and MTC-Et(395 mg, 2.101 mmol) were added directly to the flask and it wasre-capped with septum and purged again with argon. The reaction wasallowed to stir at 65° C. for several days. NO RXN

(b) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:1:50)

A 1-dram vial was equipped with stir bar, capped with septum, flamedried, and nitrogen purged. Sn(OTf)₂ (0.17 mL, 0.0124 M in ethylacetate) and benzyl alcohol (0.17 mL, 0.611 M in ethyl acetate) wereadded to the vial via syringe, and ethyl acetate was evaporated off vianitrogen flow. MTC-allyl (105 mg, 0.525 mmol) and MTC-Et (395 mg, 2.101mmol) were added and allowed to stir at 70° C. for a week. NO RXN

(c) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:1:50)

A 1-dram vial was equipped with stir bar, capped with septum, flamedried, and nitrogen purged. Sn(OTf)₂ (0.17 mL, 0.0124 M in ethylacetate) and benzyl alcohol (0.17 mL, 0.611 M in ethyl acetate) wereadded to the vial via syringe, and ethyl acetate was evaporated off vianitrogen flow. MTC-allyl (105 mg, 0.525 mmol) and MTC-Et (395 mg, 2.101mmol) were added and allowed to stir at 80° C. for a week. NO RXN

(d) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:2:50)

A 1-dram vial was equipped with stir bar, capped with septum, flamedried, and nitrogen purged. Sn(OTf)₂ (0.34 mL, 0.0124 M in ethylacetate) and benzyl alcohol (0.17 mL, 0.611 M in ethyl acetate) wereadded to the vial via syringe, and ethyl acetate was evaporated off vianitrogen flow. MTC-allyl (105 mg, 0.525 mmol) and MTC-Et (395 mg, 2.101mmol) were added and allowed to stir at 70° C. for a week. Crashed outin hexanes to yield polymer (˜40% conversion, PDI=1.08).

(e) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:3:50)

A 1-dram vial was equipped with stir bar, capped with septum, flamedried, and nitrogen purged. Sn(OTf)₂ (0.34 mL, 0.0124 M in ethylacetate) and benzyl alcohol (0.17 mL, 0.611 M in ethyl acetate) wereadded to the vial via syringe, and ethyl acetate was evaporated off vianitrogen flow. MTC-allyl (105 mg, 0.525 mmol) and MTC-Et (395 mg, 2.101mmol) were added and allowed to stir at 70° C. for 4 days.

(f) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:4:50)

A 1-dram vial was equipped with stir bar, capped with septum, flamedried, and nitrogen purged. Sn(OTf)₂ (0.68 mL, 0.0124 M in ethylacetate) and benzyl alcohol (0.17 mL, 0.611 M in ethyl acetate) wereadded to the vial via syringe, and ethyl acetate was evaporated off vianitrogen flow. MTC-allyl (105 mg, 0.525 mmol) and MTC-Et (395 mg, 2.101mmol) were added and allowed to stir at 70° C. for 3 days.

(g) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:1:50)

A 1-dram vial was equipped with stir bar, capped with septum, flamedried, and nitrogen purged. Sn(OTf)₂ (0.17 mL, 0.0124 M in ethylacetate) and benzyl alcohol (0.17 mL, 0.611 M in ethyl acetate) wereadded to the vial via syringe, and ethyl acetate was evaporated off vianitrogen flow. MTC-allyl (105 mg, 0.525 mmol) and MTC-Et (395 mg, 2.101mmol) were added and allowed to stir at 90° C. for a week. NO RXN

(h) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:10.6:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (18.5 mg, 0.044mmol) was weighed directly into the flask. The flask was sealed withrubber septum, argon purged and set to stir in a 70° C. oil bath. Benzylalcohol (22 uL, 0.210 mmol) was added to the flask via microsyringe andallowed to stir for 5 minutes. MTC-allyl (210 mg, 1.050 mmol) and MTC-Et(790 mg, 4.202 mmol) were added directly to the flask and it wasre-capped with septum and purged again with argon. The reaction wasallowed to stir at 70° C. overnight. To quench the reaction, methanolwas added and residual monomers were removed by crashing out the polymerin a vortexing solution of hexanes two times to yield slightly off-whitepolymer (0.791 g, NMR Mn=6095, 18.1% allyl, 81.9% ethyl).

(i) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:4:50)

Procedure same as described elsewhere herein with the difference beingthat 7.0 mg Sn(OTf)₂ was used (0.017 mmol). Reaction took ˜90 hours (NMRMn=4,887, 82.2% ethyl, 17.8% allyl).

(j) Synthesis of Poly(20% MTC-allyl, 80% MTC-Et)([MON]:[CAT]:[INIT]=1250:4:50)

A 25 mL round bottom flask was equipped with a stir bar, capped with arubber septum, argon purged and flame dried. Sn(OTf)₂ (8.0 mg, 0.0192mmol) was weighed directly into the flask, capped with septum, and argonpurged again. Benzyl alcohol (22 uL, 0.210 mmol) was added to the flaskvia microsyringe and allowed to stir in 70° C. oil bath for 30 minutes.MTC-Et (790 mg, 4.202 mmol) and MTC-allyl (210 mg, 1.050 mmol) werequickly added to the reaction and flask was re-sealed with septum. Thereaction was allowed to stir at 70° C. for ˜72 hours. To quench thereaction, methanol was added, and residual monomers were removed bycrashing out the polymer in a vortexing solution of hexanes two times toyield slightly off-white polymer.

k. Poly(10% MTC-allyl, 90% MTC-Et) Nanoparticle Formation UsingThiol-Ene Cross-Linking With 3,6-dioxa-1,8-octanedithiol

3,6-dioxa-1,8-octane-dithiol (34.3 μL, 0.209 mmol) was added to asolution of poly(10% MTC-allyl, 90% MTC-Et) (100 mg, M_(n)=5.3 kDa,PDI=1.25) dissolved in CH₂Cl₂ (16.2 mL). The reaction mixture refluxedat 12 hours at 45° C. Residual dithiol was removed by dialyzing withSnakeSkin Pleated Dialysis Tubing (MWCO=10,000) against CH₂Cl₂ to yieldparticles (90 mg). ¹H NMR (400 MHz, CDCl₃/TMS, ppm) δ: The significantchange is the disappearance of the allylic protons at 5.9 and 5.3 ppmand the emergence of peaks at 3.64 ppm due to the methylene protonsadjacent to the oxygens in the crosslinker and 2.73-2.68 ppm due tomethylene protons adjacent to the sulfide functionality.

l. Poly(20% MTC-allyl, 80% MTC-Et) Nanoparticle Formation UsingThiol-Ene Cross-Linking With 3,6-dioxa-1,8-octanedithiol

3,6-dioxa-1,8-octane-dithiol (70.1 μL, 0.428 mmol) was added to asolution of poly(20% MTC-allyl, 80% MTC-Et) (100 mg, M_(n)=6.4 kDa,PDI=1.39) in CH₂Cl₂ (33.0 mL). The reaction mixture refluxed at 12 hoursat 45° C. Residual dithiol was removed by dialyzing with SnakeSkinPleated Dialysis Tubing (MWCO=10,000) against CH₂Cl₂ to yield particles(90 mg). ¹H NMR (400 MHz, CDCl₃/TMS, ppm) δ: The significant change isthe disappearance of the allylic protons at 5.8 and 5.3 ppm and theemergence of peaks at 3.64 ppm due to the methylene protons adjacent tothe oxygens in the crosslinker and 2.73-2.68 ppm due to methyleneprotons adjacent to the sulfide functionality.

m. Poly(5% MTC-Epox, 95% MTC-Et) Nanoparticle Formation UsingEpdxide-Amine Cross-Linking With 2,2′-ethylenedioxy-bis(ethylamine)

2,2′-ethylenedioxy-bis(ethylamine) (22.9 μL, 0.157 mmol) was added to asolution of poly(5% MTC-epox, 95% MTC-et) (140 mg, M_(n)=5.0 kDa,PDI=1.56) dissolved in CH₂Cl₂ (12.1 mL). The reaction mixture refluxedat 12 hours at 45° C. Residual bisamine was removed by dialyzing withSnakeskin Pleated Dialysis Tubing (MWCO=10,000) against CH₂Cl₂ to yieldparticles (130 mg). ¹H NMR (400 MHz, CDCl₃/TMS, ppm) δ: The significantchange is the disappearance of the epoxide ring protons at 3.19, 2.82,and 2.63 ppm and the emergence of peaks at 3.62-3.56 due to themethylene protons adjacent to the oxygens in the cross-linker and 3.36ppm corresponding to the protons neighboring the secondary amine of thePEG linker after cross-linking.

n. Poly(10% MTC-Epox, 90% MTC-Et) Nanoparticle Formation UsingEpdxide-Amine Cross-Linking With 2,2′-ethylenedioxy-bis(ethylamine)

2,2′-ethylenedioxy-bis(ethylamine) (27.0 μL, 0.187 mmol) was added to asolution of poly(10% MTC-epox, 90% MTC-et) (90 mg, M_(n)=5.3 kDa,PDI=1.25) dissolved in CH₂Cl₂ (14.4 mL). The reaction mixture refluxedat 12 hours at 45° C. Residual bisamine was removed by dialyzing withSnakeskin Pleated Dialysis Tubing (MWCO=10,000) against CH₂Cl₂ to yieldparticles (71 mg). ¹H NMR (400 MHz, CDCl₃/TMS, ppm) δ: The significantchange is the disappearance of the epoxide ring protons at 3.19, 2.82,and 2.63 ppm and the emergence of peaks at 3.62-3.56 due to themethylene protons adjacent to the oxygens in the cross-linker and 3.36ppm corresponding to the protons neighboring the secondary amine of thePEG linker after cross-linking.

o. Poly(20% MTC-Epox, 80% MTC-Et) Nanoparticle Formation UsingEpoxide-Amine Cross-Linking With 2,2′-ethylenedioxy-bis(ethylamine)

2,2′-ethylenedioxy-bis(ethylamine) (61.8 μL, 0.420 mmol) was added to asolution of poly(20% MTC-epox, 80% MTC-et) (100 mg, M_(n)=6.6 kDa,PDI=1.39) dissolved in CH₂Cl₂ (32.5 mL). The reaction mixture refluxedat 12 hours at 45° C. Residual bisamine was removed by dialyzing withSnakeskin Pleated Dialysis Tubing (MWCO=10,000) against CH₂Cl₂ to yieldparticles

(74 mg). ¹H NMR (400 MHz, CDCl₃/TMS, ppm) δ: The significant change isthe disappearance of the epoxide ring protons at 3.19, 2.82, and 2.63ppm and the emergence of peaks at 3.62-3.56 due to the methylene protonsadjacent to the oxygens in the cross-linker and 3.36 ppm correspondingto the protons neighboring the secondary amine of the PEG linker aftercross-linking.

p. Gel Permeation Chromatography(GPC) Traces of Poly(MAC-co-MTC-Et

FIG. 9 shows the GPC trace of poly(MAC-co-MTC-Et) with comonomer ratio5:95 (MAC:MTC-Et). The poly(MAC-co-MTC-Et) had a M_(n(GPC)) of 4.7 kDaand a PDI of 1.56.

FIG. 10 shows the GPC trace of poly(MAC-co-MTC-Et) with comonomer ratio10:90 (MAC:MTC-Et). The poly(MAC-co-MTC-Et) has a M_(n(GPC)) of 5.0 kDaand a PDI of 1.25.

FIG. 11 shows the GPC trace of poly(MAC-co-MTC-Et) with comonomer ratio20:80 (MAC:MTC-Et). The poly(MAC-co-MTC-Et) had a M_(n(GPC)) of 4.9 KDaand a PDI of 1.39.

q. Oxidation of Carbonate Copolymers

General Reaction: Oxidation of poly(MTC-allyl, MTC-ethyl)

In a 25 mL round bottom flask equipped with a stir bar, polymer (0.369g, 0.346 mmol) was dissolved in 6.8 mL dichloromethane and3-chloroperoxybenzoic acid (83.6 mg, 0.485 mmol) was added. The mixturestirred for 48 hours at room temperature. Residual 3-chloroperoxybenzoicacid was removed by extracting the polymer solution in dichloromethaneagainst aqueous sodium bicarbonate to yield polymer (NMR Mn=4941 Da,16.0% MTC-epox, 1.8% MTC-allyl, 82.2% MTC-Et).

To determine the chain length more accurately we have changed theinitiator from benzyl alcohol to 3-methyl-1-butanol. With the use ofthis initiator we have accurately prepared the molecular weight of thepolycarbonate.

Synthesis of poly(MTC-Et) with 3-methyl-1-butanol([mon]:[cat]:[init]=1250:4:50)

A 1-dram vial was equipped with a stir bar, capped with a rubber septum,argon purged and flame dried. Sn(OTf)₂ (3.5 mg, 0.008 mmol) was weigheddirectly into the vial. The vial was sealed with rubber septum, argonpurged and set to stir in a 70° C. oil bath. 3-methyl-1-butanol (11.6uL, 0.106 mmol) was added to the flask via microsyringe and thecatalyst/initiator solution was allowed to stir at 70 C for 30 minutes.MTC-Et (0.500 g, 2.657 mmol) was added to the solution and allowed tostir. Reaction began slowing down at 26 hrs so I removed from heat.Crude NMR showed 71.8% monomer conversion and Mn=3,303 Da.

Synthesis of 10 k poly(MTC-Et) with 3-methyl-1-butanol([mon]:[cat]:[init]=1250:4:25)

A 1-dram vial was equipped with a stir bar, capped with a rubber septum,argon purged and flame dried. Sn(OTf)₂ (3.5 mg, 0.008 mmol) was weigheddirectly into the vial. The vial was sealed with rubber septum, argonpurged and set to stir in a 70° C. oil bath. 3-methyl-1-butanol (5.8 uL,0.053 mmol) was added to the flask via microsyringe and thecatalyst/initiator solution was allowed to stir at 70° C. for 30minutes. MTC-Et (0.500 g, 2.657 mmol) was added to the solution andallowed to stir. Took out of oil bath after 70 hours and precipitatedinto ˜150 mL of very cold methanol to yield colorless polymer (67 mg,Mn=10,076 Da).

Kinetics of poly(MTC-Et) with 3-methyl-1-butanol([mon]:[cat]:[init]=1250:4:50)

A 1-dram vial was equipped with a stir bar, capped with a rubber septum,argon purged and flame dried. Sn(OTf)₂ (3.5 mg, 0.008 mmol) was weigheddirectly into the vial. The vial was sealed with rubber septum, argonpurged and set to stir in a 70° C. oil bath. 3-methyl-1-butanol (11.6uL, 0.106 mmol) was added to the flask via microsyringe and thecatalyst/initiator solution was allowed to stir at 70° C. for 30minutes. MTC-Et (0.500 g, 2.657 mmol) was added to the solution andallowed to stir. At each time point, a small amount of the reaction wasremoved via syringe and analyzed by NMR.

The kinetic results for poly(MTC-Et) with 3-methyl-1-butanol with a[mon]:[cat]:[init] ration of 1250:4:50 can be seen in FIGS. 12 and 13.

r. Attachement of Pep T1 Targeting Peptide to Crosslinked Polymers

(3S)-4-tert-butoxy-3-[[(2S)-2-(tert-butoxycarbonylamino)propanethioyl]amino]-4-oxo-butanoicacid (1.1 mg, 2.9 μmol) in anhydrous DMF (96 μL) stirred under argon at0° C. with N-methylmorpholine (30 μL, 0.11 M in DMF, 3.3 μmol). Isobutylchloroformate (30 μL, 0.11 M in DMF, 3.3 μmol) was added drop-wise andthe reaction was allowed to stir 2 hours. A solution of nanoparticles(20 mg, 0.10 μmol) in anhydrous DMF (2.6 mL) was then added drop-wiseand reaction was allowed to stir 24 hours at room temperature. Thereaction was purified by dialysis with Snakeskin Pleated Dialysis Tubing(MWCO 10,000) against dichloromethane. ¹H NMR (400 MHz, CDCl₃/TMS, ppm)δ: The significant change is the appearance of the tert-butoxy protonsat 1.50 and 1.43 ppm due to the peptide attachment. The reaction isillustrated below.

s. Encapsulation of Paclitaxel

A solution of nanoparticle (40 mg) and paclitaxel (8.8 mg) in DMSO (0.10mL) was added drop-wise to a vortexing solution of aqueous 1% d-atocopherol polyethyleneglycol (1000) succinate (Vit E-TPGS, 20 mL). Theresulting precipitation was centrifuged at 7800 rpm for 20 minutes andsupernatant was removed. The precipitation was freeze-dried to yield aclear, viscous liquid.

t. Polycarbonate Hydrogel Formation Via Thiolene Click

A mixture of poly(MEC, MAC) (100 mg, 0.10 mmol) and2,2-dimethoxy-2-phenylacetophenone (DMPA, 5.4 mg, 0.02 mmol) wasdissolved in DMF (0.10 mL) and allowed to stir at room temperature.3,6-dioxa-1,8-octane-dithiol (17 uL, 0.10 mmol) was added and reactionwas exposed to UV light (365 nm) for 5 minutes. The resulting gel waswashed in sequence with methanol and dichloromethane and allowed to dryovernight in vacuo to yield a colorless gel. The reaction is illustratedbelow.

u. Polycarbonate/Hydroxyl Terminated Polymer Macroscopic NetworkFormation Via Thiolene Click

The poposed reaction is illustrated below.

v. Polycarbonate/Hdroxyl Terminated Macroscopic Network

Formation Via Thiolene Click and Zinc Acetate Rearrangment

This poposed reaction is illustrated below.

w. General MEC Homopolymer Synthesis

A 25-mL round bottom flask was equipped with stir bar, capped withrubber septum, flame dried and nitrogen purged. Sn(OTf)₂ (7.0 mg, 0.0168mmol) was added to the flask, and the flask was nitrogen purged oncemore. 3-methyl-1-butanol (5.8 μL, 0.0531 mmol) was added to the reactionflask via microsyringe, and the catalyst/initiator mixture was allowedto stir at room temperature for 30 minutes. MEC (0.500 g, 2.657 mmol)was added to the flask and allowed to stir in 70° C. oil bath for 87hours. Polymer was purified by precipitation into methanol or by usingSpectra/Por dialysis membrane (MWCO=1,000 Da) againstdichloromethane/methanol to yield colorless polymer (TheoreticalMn=18,800 Da, NMR Mn=18,400 Da, PDI=1.11 yield=0.460 g). ¹H NMR (400MHz, CDCl₃/TMS, ppm) δ: 4.40-4.15 (m, —OC(O)OCH₂), 1.30-1.22 (m, CH₃,—OCH₂CH₃), 0.93-0.91 (d, 3-methyl-1-butanol, —OCH₂CH₂CH(CH₃)₂).

x. General MEC, MAC Copolymer Synthesis

A 1-dram vial was equipped with stir bar, capped with rubber septum,flame dried and nitrogen purged. Sn(OTf)₂ (3.5 mg, 0.0084 mmol) wasadded to the vial, and the vial was nitrogen purged once more.3-methyl-1-butanol (11.4 μL, 0.105 mmol) was added to the reaction vialby microsyringe, and the catalyst/initiator solution was allowed to stirat room temperature for 30 minutes. MEC (0.395 g, 2.099 mmol) and MAC(0.105 g, 0.5245 mmol) were added to the vial and allowed to stir in 70°C. oil bath for 71 hours. Polymer was purified by precipitation intomethanol or by dialysis using Spectra/Por dialysis membrane (MWCO=1,000Da) against methanol/dichloromethane to yield colorless polymer(Calculated Mn=4,800 Da, NMR Mn=6,500 Da, PDI=1.11, yield=0.359 g)theoretical allyl incorporation=20.0%, actual allylincorporation=19.0%). ¹HNMR (400 MHz, CDCl₃/TMS, ppm) δ: 5.91-5.85 (m,—OCH₂CHCH₂), 5.34-5.23 (m, —OCH₂CHCH₂), 4.64-4.62 (m, —OCH₂CHCH₂),4.40-4.15 (m, MAC & MEC, —OC(O)OCH₂), 1.30-1.22 (m, MAC & MEC, CH₃; MEC,—OCH₂CH₃), 0.93-0.91 (d, 3-methyl-1-butanol, OCH₂CH₂CH(CH₃)₂). ¹³C NMR(400 MHz, CDCl₃/TMS, ppm) δ: 174.1, 172.1, 154.9, 154.4, 131.7, 118.5,68.6, 65.9, 64.7, 61.2, 50.8, 48.2, 46.5, 24.8, 22.4, 17.5, 14.1.

y. Number Average Molecular Weight (MN)—Monomer Conversion Experiment

The MEC homopolymers were prepared as described elsewhere herein. Atpredetermined time points, a small amount of the polymerization wasremoved and analyzed immediately by ¹HNMR. The reaction yielded theresults shown in FIG. 14.

REFERENCES

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It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otheraspects of the invention will be apparent to those skilled in the artfrom consideration of the specification and practice of the inventiondisclosed herein. It is intended that the specification and examples beconsidered as exemplary only, with a true scope and spirit of theinvention being indicated by the following claims.

What is claimed is:
 1. A method of crosslinking polycarbonatescomprising: (a) providing a first epoxy functionalized polycarbonate anda second epoxy functionalized polycarbonate; and (b) crosslinking thefirst epoxy functionalized polycarbonate and the second epoxyfunctionalized polycarbonate via a crosslinker, wherein the first epoxyfunctionalized polycarbonate comprises residues having the structures:


2. The method of claim 1, wherein the epoxy functionalizations arepresent as groups pendent from the polycarbonate backbone.
 3. The methodof claim 1, wherein crosslinking thereby forms a particle.
 4. The methodof claim 3, wherein the particle is a nanoparticle.
 5. The method ofclaim 1, wherein the second epoxy functionalized polycarbonate comprisesresidues having the structure:


6. The method of claim 5, wherein the second epoxy functionalizedpolycarbonate further comprises residues having the structure:


7. The method of claim 1, wherein the crosslinker comprises at least twomoieties that can be reacted with the epoxy functionalities.
 8. Themethod of claim 7, wherein the moieties are amine moieties.
 9. Themethod of claim 1, wherein the crosslinker is

wherein n is from 1 to
 1000. 10. The method of claim 1, wherein thecrosslinker is


11. The method of claim 7, wherein the moieties are thiol moieties. 12.The method of claim 1, wherein the crosslinker is

wherein n is from 1 to
 1000. 13. The method of claim 1, wherein thecrosslinker is


14. The method of claim 1, wherein the first epoxy functionalizedpolycarbonate and the second epoxy functionalized polycarbonate have thesame structure.
 15. The method of claim 1, wherein the first epoxyfunctionalized polycarbonate and the second epoxy functionalizedpolycarbonate are copolymers.
 16. A method of crosslinkingpolycarbonates comprising: (a) providing a first epoxy functionalizedpolycarbonate and the second epoxy functionalized polycarbonate; and (b)crosslinking the first epoxy functionalized polycarbonate and the secondepoxy functionalized polycarbonate via a crosslinker, wherein the firstepoxy functionalized polycarbonate is

wherein y is 1 to 1000, and z is 1 to
 1000. 17. The method of claim 16,wherein the first epoxy functionalized polycarbonate comprises at least75% by weight of residues having a structure:


18. The method of claim 17, wherein the crosslinked polycarbonate hasthe structure:

wherein each y is individually 1 to 1000, each z is individually 1 to1000, and n is 1 to
 1000. 19. A compound having a structure

wherein each y is individually 1 to 1000, each z is individually 1 to1000, and n is 1 to
 1000. 20. A composition comprising the compound ofclaim 19.